In 1990, we identified and began to characterize a new chronic disorder we have termed autoimmune lymphoproliferative syndrome, or ALPS. It is characterized by chronic non-malignant adenopathy and splenomegaly and a variety of autoimmune phenomena.Through our investigations of nearly 250 members of 71 families, we have learned to identify and diagnose the syndrome and treat most of its complications effectively. We have documented a number of immunologic abnormalities in ALPS patients, including disordered regulation of cytokines including IL-10.In vitro studies with human cells and cell lines showed that ALPS is associated with inherited defects in lymphocyte apoptosis. About 75% of patients possess specific functional mutations in the gene encoding Fas, a protein that triggers apoptosis, the programmed death of lymphocytes. Because Fas is critical to lymphocyte apoptosis, the cells persist when no longer appropriate&#61507;leading to accumulation of cells infiltrating tissues&#61507;including cells with reactivity against self-antigens. Initial studies showed that Fas is expressed on the surfaces of our patients&#61501; cells, but some of it is abnormal, arising from one mutated copy of the pair of Fas genes. The defective Fas protein that is expressed interferes with the function of the normal Fas protein. Many relatives of ALPS patient have Fas mutations but are completely well. Recent studies showed that the risk of manifesting clinical features of ALPS is greatest in individuals who inherit mutations in exon 9 encoding the cytoplasmic signaling domain of Fas.Fas mutations are not responsible for ALPS in 15 of our affected families. Mutations in the fas-ligand are responsible for disease in 2 families elsewhere. Mutations in caspase 10 (MCH-4) are associated with defective apoptosis and ALPS in 2 other families. Other genetic defects muist underlie ALPS in our remaining families. - Apoptosis, Fas, caspases, lymphoma, cytokines, genetic studies, autoimmune lymphoproliferative syndrome - Human Subjects & Human Subjects: Interview, Questionaires, or Surveys Only